Engineering the next-generation of antibody therapeutics requires cutting-edge technologies and innovative protocols. Reducing development time, while ensuring therapeutic efficacy, is essential to quickly generate stable antibodies that possess high affinity. Novel discovery platforms are generating antibodies with desirable properties, such as enhanced PK (pharmacokinetics), and prolonged half life, while computational tools are providing insights through modeling and in silico screening.

Experts will present Case Studies from their therapeutic antibody development programs, as well as discuss innovative engineering and analytical strategies. How to determine the precise epitope of therapeutic antibodies will also be addressed along with specifics about engineering Fc mutations and reducing immunogenicity. How will the next generation of improved antibody therapeutics be created? Find out at the 9th annual "Antibodies for the 21st Century" meeting, and join with Key Leaders from around the world to discuss the latest advances in the development of Therapeutic Antibodies.

Although the first regulatory approval of a monoclonal antibody (mAb) for therapeutic use in human occurred with approval of muromonab-CD3 in 1986, it was approval and subsequent commercialization of rituximab, palivizumab, inflixumab, and trastuzumab in the late 1990s and adalimumab, cetuximab and bevicizumab in the early 2000s that validated mAbs as medically and financially viable therapeutics. This collection of highly successful biologic products was derived via a set of technology platforms utilized in discovery of the vast majority of marketed and clinical-phase antibody therapeutics generated to date. Although 2012 mAb (and mAb-derived) market sales are expected to exceed $50 billion and the compound annual growth rate is estimated to exceed 8% through 2016 in contrast to the flat or somewhat negative sales growth expectations for small molecules over this time frame, the antibody market is rapidly maturing with future growth prospects dependent upon next-generation modalities such as multi-specifics and antibody-drug conjugates. Trends in therapeutic antibody discovery and emerging modalities will be discussed and selected recent clinical data highlighted.

Antibodies produced as therapeutic candidates represent a variety of sequences generated by recombination and somatic hypermutation. Quite often this mechanism, so robust in generating antibodies of desired binding properties and efficacy, leads to antibodies that exhibit undesirable properties. Proactive sequence and structure analysis, coupled with knowledge of sequence and structure motifs, allows for the early engineering of variants that can avoid many of the later stage issues that arise with antibody therapeutics.

We determined the crystal structures of two naturally occurring Fab fragments containing ultralong CDR3s and found they have unusual beta-stranded “stalk” and disulfide bonded “knob” features which protrude from the antibody surface. Deep sequencing of ruminant B-cells analysis suggested enormous diversity in the knob domain, with a wide range of different disulfide bonded structures that could potentially form. Using this structural information, these ultralong CDR3s were humanized and engineered to bind both GPCR and ion channel targets.

Two-in-One antibodies are generated by evolving the antigen-binding site on Fab arm of a mono-specific antibody to add on a second specificity, and thus can be produced and developed as conventional antibodies. The proof of concept for the technology is based on Herceptin, which was engineered to also bind and block VEGF with high potency. In clinical phase II is an EGFR/HER3 two-in-one antibody that showed a broader range of efficacy in inhibiting the growth of epithelial tumor models than a mono-specific EGFR or HER3 antibody alone.

11:45 OMP-59R5: A Novel Therapeutic Antibody in Clinical Development for Patients with Cancer

OMP-59R5 (Anti-Notch2/3) is a fully human monoclonal antibody that targets the Notch2 and Notch3 receptors. Preclinical studies have demonstrated that OMP-59R5 exhibits two mechanisms of action: (1) by downregulating Notch pathway signaling, OMP-59R5 appears to have anti-Cancer Stem Cell effects, and (2) OMP-59R5 affects pericytes, impacting stromal and tumor microenvironment. The program is also currently completing a single-agent Phase Ia trial in advanced solid tumor patients. Additionally, a Phase 1b/2 clinical trial called “ALPINE” (Antibody therapy in first-Line Pancreatic cancer Investigating anti-Notch Efficacy and safety), has been initiated. In ALPINE, OMP-59R5 is being tested in combination with gemcitabine in first-line advanced pancreatic cancer patients. Pre-clinical and clinical data will be presented.

12:15pm Close of Morning Session

12:30 LUNCHEON PRESENTATION

High Density Protein Microarray and Its Application in Developing Ultra-Specific mAbs

Donghui Ma, Ph.D., Director, Immunology, OriGene Technologies, Inc.

Antibody specificity is of pivotal importance for its use, especially in diagnostic and therapeutic applications. Currently no technologies have been established for antibody specificity validation. Here we will showcase OriGene’s novel platform of high density protein microarray technology to test antibody specificity. Using such platform, OriGene has successfully created a new line of ultra-specific mAbs, TrueMAB®, for multiple diagnostic targets, including HER2 and ERCC1. Sample cases will be discussed.

We used surface plasmon resonance and isothermal titration calorimetry to understand the interaction and identify IgG domains distal from the putative FcRn binding site that contribute to IgG binding to FcRn. Understanding these interactions or binding behaviors would be useful in optimizing monoclonal antibodies for in vivo half-life and help choose best lead molecule in the lead optimization phase of drug discovery. We are the first ones to dissect the contribution of IgG domains in IgG:FcRn interactions.

2:35 Developability: Predicting, Avoiding and Reducing Immunogenicity and the Risk of Failure of Biotherapeutics

We present the in silico and in vitro tools used to assess Immunogenicity and stability and reduce aggregation showing the application and benefit of these tools during the development of biotherapeutics.

Antibodies and non-antibody biotherapeutics are glycooptimized in respect to bioactivity, bioavailability, immunogenicity and patient coverage obtaining manifold improved Biobetters. Three antibody and one non-antibody products are now in clinical studies. Among the three antibody molecules are one new biological entity directed against a novel target as well as the biobetter molecules CetuGEX™ and TrasGEX™ which are improved forms of cetuximab and trastuzumab. Data from pre-clinical, clinical and production technologies will be presented.

3:35 A Uniform Framework for Computer-Aided Biologics DesignChristopher R. Corbeil, Ph.D., Research Scientist, Chemical Computing GroupProtein engineering plays a pivotal role in modulating the function, activity and physical properties of biologics. Representative strategies employed in protein engineering include rationale protein design and directed evolution. In general, disparate work has been done in applying computer-aided biologics design (CABD) to protein engineering for the development of novel biological therapeutics. Here, we establish a unified framework of protein engineering tools and investigate its applicability to modulation of protein properties: affinity and stability.

4:05 Refreshment Break

4:15 Advancements in High-Throughput Biophysical Technologies: Applications for Characterization and Screening During Early Formulation Development and Engineering of Monoclonal Antibodies

Hardeep Samra, Ph.D., Scientist II, Formulation Sciences, MedImmune

4:45 Insights into IgG4 and the Stability Thereof

Shirley Peters, Research Scientist, UCB Pharma

The IgG4 isotype may be employed as a biotherapeutic when a target antigen simply needs to be neutralized or prevented from binding without risk of inducing effector functions. However, IgG4 has shown to display some propensity to increased aggregation as well as forming bispecific monovalent IgG4 in vivo. We have generated mutants of a human IgG4 in order to improve on thermal stability and to probe the interactions that potentially determine the unique features observed for IgG4.

5:15 Close of Session

5:30-6:30 Networking Reception in the Exhibit Hall with Poster Viewing